Endocrine Abstracts

Recognizable features of a genetic predisposition to cancer are the development of 1 or more malignancies at an earlier than expected age and/or familiar clustering of cancer. Although nonmedullary thyroid carcinoma (NMTC) meets these characteristics (eg, 16% diagnosed below 35 years, increased risk for a second primary tumour and a 3- to 10-fold increased risk in relatives), most NMTC cases remain genetically unexplained. Familial nonmedullary thyroid cancer constitutes 3% to 9% of all thyroid cancers and is recognized as a distinct clinical entity, with heritability partially attributable to tumour predisposition syndromes such as PTEN hamartoma tumour syndrome, Carney complex, familial adenomatous polyposis, DICER1 syndrome, and Werner syndrome. In addition, genome-wide association studies and family-based case series have suggested a variety of possible associated genes (eg, DIRC3, FOXE1, NRG1, SMAD3, SRGAP1, SRRM2, and TITF-1/NKX2.1). Furthermore, recent studies indicate that NMTC heritability may be partly polygenic. Besides important clinical implications for the index patient, identification of a causative germline variant also facilitates cascade testing and surveillance of relatives, allowing early identification of (pre)malignant conditions. Currently no clear guidelines for genetic testing for NMTC are available. An important unanswered question is whether patients with NMTC should undergo genetic testing and, if so, which type of genetic test (eg, single gene/gene panel/whole exome or genome sequencing) should be performed. Recent genetic screening of a large, unbiased paediatric NMTC cohort detected a relatively high prevalence (13%) of P/LP germline variants in well-known tumour predisposing genes. This prevalence led us to recommend genetic counselling for all patients with childhood NMTC.